Nicotine dependence remains the leading cause of preventable mortality in the United States, accounting for nearly 450,000 deaths annually. Tobacco smoking cessation offers clear health benefits and partially effective cessation pharmacotherapies exist. However, 65-80 percent of initially abstinent smokers relapse within 12 months. Since smoking cue reactivity is strongly associated with craving and, in smokers trying to quit, with relapse, discovering treatments that reduce smoking cue reactivity may help promote sustained tobacco abstinence. !n preclinical studies, dopamine (DA) D3 receptor antagonists effectively reduced nicotine and other drug- conditioned responses including cue-induced reinstatement of nicotine seeking. Therefore, D3 receptors may moderate nicotine and other drug cue-reactivity and may play a role in cue-induced relapse. This Exploratory Developmental R21 project aims to determine whether D3 receptors are elevated in smokers and whether correlations exist between D3 receptor binding and functional MRI (fMRI) reactivity to smoking cues, which has been associated with smoking relapse vulnerability. Neuroimaging measures will be collected concurrently in otherwise healthy nicotine-dependent smokers and age-matched nonsmokers using a 3 Tesla MRI scanner configured to conduct fMRI and Positron Emission Tomography (PET). We propose to measure PET D3 receptor binding using radiolabeled [11C]-(+)-PHNO, which has a relatively higher affinity for D3 receptors over other radiotracers labeling D2/D3 receptors. Prior studies reported that D3 antagonist treatment decreased [11C]-(+)-PHNO binding in brain regions involved in reward learning including the substantia nigra (SN), globus pallidus (GP), and ventral pallidum (VP). Thus, SN, GP, and VP D3 receptors may play a role in relapse, possibly by moderating behavioral responses to drug cues. Because preclinical and clinical evidence suggest that stimulant exposures increase D3 receptor levels, we hypothesize that PET [11C]-(+)-PHNO binding in SN, in which binding is almost exclusively to D3 receptors, will be elevated in smokers when compared to nonsmokers. We also hypothesize that within smokers, SN [11C]-(+)-PHNO binding will be positively correlated with fMRI smoking cue reactivity in brain areas previously shown to exhibit high smoking cue fMRI reactivity, including anterior insula, amygdala, and dorsal striatum. Validation of these hypotheses may help clarify mechanisms underlying relapse vulnerability and may help identify smokers who would particularly benefit from D3 antagonist treatment, thereby enabling a personalized medicine approach. PUBLIC HEALTH RELEVANCE: Nicotine dependence remains the leading cause of preventable mortality in the United States. This Exploratory Developmental R21 program aims to determine whether smokers exhibit increased levels of dopamine D2/D3 receptors and whether there is an association between D2/D3 level, as measured with Positron Emission Tomography (PET), and smoking cue functional MRI reactivity, which when increased predicts heightened relapse vulnerability. PET and fMRI scans will be acquired simultaneously on an MRI scanner fit with a PET imaging insert. Program findings may lead to new smoking cessation and relapse prevention treatments.